The present invention is drawn to compositions, and methods of making and administering compositions, that can be used for mineral supplementation. More specifically, the present invention is drawn to dimetalhydroxy malates.
Magnesium is a mineral that is needed in humans and other warm-blooded animals for bone, protein, and fatty acid formation. Magnesium is also involved in the formation of new cells, activating certain vitamins, relaxing muscles, clotting blood, and forming ATP. People with diabetes often have magnesium levels that are lower than normal compared with those who have normal glucose tolerance. Supplementation of magnesium can help maintain health in some of these areas, as well as help in overcoming some of these problems. Typically, many people do not consume enough magnesium in their diets.
Calcium, on the other hand, is the most abundant mineral in the human body. Of the calcium contained in the average body, about 99% is located in the bones, including the teeth. Calcium is needed to form bones and teeth and is also required for blood clotting, transmission of signals in nerve cells, and muscle contraction. Calcium supplementation is believed to reduce the incidence of osteoporosis.
Choosing a form of magnesium and/or calcium for supplementation has been a source of some confusion in the industry. Calcium carbonate is one form of calcium that is widely used, but is not believed to be absorbed as well as some other forms. Calcium citrate provides a form that is believed to be better absorbed than calcium carbonate. Calcium citrate/malate (CCM) is believed to be absorbed more fully than carbonate as well.
Other divalent minerals, such as zinc, copper, iron, and manganese, are also known to be important to the human diet, and can be administered in a supplemental form. For example, the trace mineral zinc is known to be involved in the transport of vitamin A, taste, wound healing, and fetal development. Zinc also plays a part in the correct functioning of many enzymes, hormones including insulin, genetic material, and proteins. Copper, on the other hand, plays a role in the absorption of iron, and is part of many enzymes. Additionally, iron is necessary for production or hemoglobin and oxygenation of red blood cells, builds up blood quality, and increases resistance as well as increasing energy production. Benefits of manganese include improvement of memory and reflexes, reducing of fatigue, and promoting proper development of thyroid hormones, skeletal, reproductive, and central nervous systems.
Malic acid is a dicarboxylic acid that is naturally occurring. Malic acid plays a role in the complex process of deriving ATP (the energy currency that runs the body) from food. Malic acid is found in a wide variety of fruits (including richly in apples) and vegetables. As malic acid is already found abundantly in humans and other warm-blooded animals, it can be administered without adverse affects. Further, there is some evidence that malic acid supplementation can be helpful to human nutrition.
It has been recognized that the use of certain complexes can provide a quantity of a bioavailable form of certain nutritionally relevant metals. Specifically, a composition meeting this criterion can have the structure: 
wherein M and Mxe2x80x2 are each independently a nutritionally relevant divalent metal.
Additionally, a method of administering a high content of a divalent essential metal in a bioavailable form to a warm-blooded animal is also provided. The method comprises the step of administering the composition of Formula 1 to a warm-blooded animal.
In another embodiment, a method of making a bioavailable divalent metal-containing complex, such as that shown in Formula 1, can comprise the step of reacting malic acid with a divalent metal-containing composition at a 1:2 molar ratio, wherein the divalent metal of the divalent metal-containing composition is a nutritionally relevant divalent metal.
Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein because such process steps and materials may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only. The terms are not intended to be limiting because the scope of the present invention is intended to be limited only by the appended claims and equivalents thereof.
It is to be noted that, as used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
The term xe2x80x9cnutritionally relevant metalxe2x80x9d or xe2x80x9cnutritionally relevant divalent metalxe2x80x9d means any divalent metal that can be used as part of a nutritional supplement, is known to be beneficial to humans and other warm-blooded animals, and is substantially non-toxic when administered in traditional amounts, as is known in the art. Examples of such metals include copper, zinc, manganese, iron, magnesium, calcium, and the like.
When referring to a dimetalhydroxy malate (such as dicalciumhydroxy malate, dimagnesium malate, etc.), the xe2x80x9cdixe2x80x9d portion of the name refers to two +M(OH) or metalhydroxy groups, one being complexed to a first carboxyl group of the malate ion, and the other being complexed to a second carboxyl group of the malate ion. Thus, each metal is complexed to the malate ion and is also complexed to its own hydroxy group to charge balance the metal. The metals that can be used include divalent nutritionally relevant metals, and two of the same metal or two different metals can be present at each carboxyl group of the malate ion.
The term xe2x80x9cdivalent metal-containing compositionxe2x80x9d shall mean compositions used to react with malic acid to form a dimetalhydroxy malate in accordance with embodiments of the present invention, wherein the metal can be two of the same metal, or two different metals. Elemental divalent metals, divalent metal hydroxides, divalent metal oxides, and divalent metal carbonates are included.
In one embodiment of the present invention, a composition having the structure: 
is provided, wherein M and Mxe2x80x2 are each independently a nutritionally relevant divalent metal. In other words, M and Mxe2x80x2 can be the same divalent metal, or can be different divalent metals. Though any nutritionally relevant divalent metal can be used, calcium, magnesium, copper, zinc, manganese, and iron provide examples of desired metals for use.
The present invention is also drawn toward a method of administering a high content of a metal in a bioavailable form to a warm-blooded animal. In one embodiment, the composition of Formula 1 above can be administered to the warm-blooded animal, such as a human. The administration can be by one of many known administration routes, including oral administration. If formulated for oral delivery or consumption, such a composition can be incorporated into many delivery vehicles, including tablets, capsules, foods, drinks, dry drink mixes, or other substances acceptable for oral consumption. Tablets may be chewable or non-chewable. A food delivery vehicle may be, for example, in the form of food bars or incorporated into dairy products. Drinks may be in the form of sports drinks, fruit drinks, citrus drinks, carbonated drinks, and other suitable drink mediums. Dry drink mixes may be in the form of a fruit mix and/or citrus mix or other particulate drink mixes. No matter what the vehicle of delivery, the compositions of the present invention are very stable, and thus, can be coadministered with many other supplements known in the art. For example, the compositions of the present invention can be coadministered with mineral salts and/or mineral amino acid chelates in drink mixes, supplement tablets or capsules, or food items.
In another embodiment, a method of making a bioavailable divalent metal-containing complex can comprise the step of reacting malic acid with one or more divalent metal-containing compositions at a 1:2 molar ratio, wherein the divalent metal of the composition is a nutritionally relevant divalent metal. This can be done in the presence of excess water, or can be done by providing a particulate blend of the malic acid and the divalent metal-containing composition, and then adding small amounts of water stepwise. The bioavailable divalent metal-containing complex formed can comprise the structure of Formula 1 above.
There are at least four specific reaction schemes that can be followed in carrying out the method of making the composition of Formula 1, though these reaction schemes are not intended to be limiting. A first reaction scheme is depicted below in Formula 2, as follows: 
In the above reaction scheme, M can be any nutritionally relevant divalent metal, including iron, magnesium, calcium, magnesium, zinc, or copper. Two extra water molecules are formed as the hydrogen atoms are liberated from the malic acid and react with the excess hydroxy groups from the two metal hydroxides. A second reaction scheme is depicted below in Formula 3, as follows: 
In the above reaction scheme, M can be any nutritionally relevant divalent metal, including iron, magnesium, calcium, magnesium, zinc, or copper. When a metal oxide is used, no extra water molecules are formed as in Formula 2 above. In a third reaction scheme, Formula 4 is provided as follows: 
In the above reaction scheme, M can be any nutritionally relevant divalent metal, including iron, magnesium, calcium, magnesium, zinc, or copper. When an elemental metal is used, the extra oxygen atoms that are present in the resulting product come from the water, and two hydrogen atoms remain, either to remain in ionic form in the water, or to form H2 gas. Formula 5 provides a fourth reaction scheme that can be used in preparing the compositions of the present invention, as follows: 
In the above reaction scheme, M can be any nutritionally relevant divalent metal, including iron, magnesium, calcium, magnesium, zinc, or copper. When a metal carbonate is used, two carbon dioxide molecules are formed.
Though each of the reaction schemes of Formulas 2-5 are provided such that a single metal (M) is used in the reaction, combinations of any two metals can also be present on a single malate ion. In other words, by modifying the reaction schemes to include two different compositions of metal oxides, hydroxides, carbonates, or elemental metals, such compositions can be formed as would be apparent to one skilled in the art after considering the present disclosure. For example, in one embodiment, rather than using 2 molar equivalents of calcium hydroxide in the reaction scheme of Formula 2, one can use one molar equivalent of calcium hydroxide and one molar equivalent of zinc hydroxide to obtain such a result. If such a composition were prepared, three possible compositions could be present in the preparation, including 1) dicalciumhydroxy malate, 2) dizinchydroxy malate, and 3) calciumhydroxy zinchydroxy malate. Examples of the preparation of compositions having one type of metal at both carboxyl groups of the malate ion, or two different metals at each carboxyl group of the malate ion will be provided below.
With respect to each of the compositions and methods of the present invention, once formed in an aqueous solution, the product can be dried to form a particulate composition. Desired particulate sizes can be formed using one of a number of drying methods, including spray drying, drum drying, tray drying, tunnel drying, freeze drying, compressed air drying, and oven drying, among others as is known in the art.
In the above Formulas 2-5, the reactions shown are in the presence of excess water, which can be followed by a drying step. However, the same reaction schemes can be prepared in the absence of excess water. In other words, small amounts of water can be added incrementally to the reactants to form a granular product, thereby removing the need for a spray-drying step (or other equivalent drying step), if a dried product is desired. For example, the reacting step can be carried out by (a) dry blending particulate malic acid and a particulate divalent metal-containing composition to form a particulate blend; (b) adding water to the particulate blend in an amount that causes a partial reaction between the malic acid and the divalent metal-containing composition, (c) allowing the particulate blend to substantially react in the presence of the amount of water; and (d) repeating step (b) and step (c) until a granular product is formed that is substantially fully reacted.
In one embodiment, this process can be carried out by first, combining the reactants, i.e., malic acid and divalent metal-containing composition, in dry form and mixing them together, such as in a Ribbon Blender or the like. The mixing device can be continuously run during this process for acceptable results. A fraction of the total amount of water needed to effectuate the reaction can then be slowly added, such as by spraying the water into the particulate mixture. The water is preferably sprayed, as dumping water onto the reactants tends to cause over reaction and clumping. In one embodiment, from 5% to 20% of the water necessary to complete the reaction can be added or sprayed on at a time, allowing reaction time to occur between each further water addition. A water jacket can be used with the reaction vessel to keep the reactants cool.
As the water is added in small amounts stepwise, the product will progress toward completion. At each stage of added water, the reactants tend to become sponge-like and raise in level within the mixer. When the reaction nears completion for a given stage, the heat lowers, the product level falls, and the density increases, returning the product to a more granular state. Next, more water is added, and a similar phenomenon reoccurs (typically to a lesser extent at each water addition step). At each stage, the product should be allowed to react until the reaction is substantially complete. Once the heat and expansion is substantially absent when water is added, the process is done. At this point, if water is continued to be added, the product will begin to change back to a powder form, which is undesirable. Therefore, care should be taken to stop adding water when desired granulation is present, and the reaction has substantially stopped. Upon completion of the process, the product can be removed from the mixing device, stored in either a cool or warm room for drying, and optionally, ground to a desired particle size.